Compounds with selectivity for certain cancers

Abstract

This technology provides an elucidation of the translational potential of the targeted anticancer compound Steviokine (I) and a determination of its biological properties. A series of compounds having an alkyne substituent were prepared. Steviokine and derivatives thereof were found to have high selectivity in an expanded panel of cancer cell lines. (Steviokine).

Description

[0001]COMPOUNDS WITH SELECTIVITY FOR CERTAIN CANCERS RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No.63 / 516,286, filed July 28, 2023, which is incorporated herein by reference. BACKGROUND OF THE INVENTION Cytotoxic chemotherapies are well-known for their debilitating side effects, largely the result of engaging targets present in both cancerous and non-cancerous cells. As such, the past two decades have seen a marked rise in the development of targeted anticancer therapeutics, for example, from 2009 to 202043% approved drugs for cancer were classified as targeted small molecules, while only 7% were cytotoxins. In the development of targeted therapeutics for cancer, one trait that is a portent of clinical success is the selective killing of a subset of cancer cell lines in culture; that is, high activity against select cancer cell lines in culture and low activity against others. Typically, successful targeted therapeutics will display a 100-1,000-fold difference in activity between susceptible and non-susceptible cells. Several examples of successful frontline therapies displaying such high selectivity in large cancer cell line panels in culture include the BCR-ABL inhibitor imatinib, the KRAS G12C inhibitor sotorasib and the BRAF V600E inhibitor vemurafenib. Despite the success of cell line-selective targeted therapeutics against select types of cancer in the clinic, cytotoxic chemotherapies are still a mainstay of current cancer therapy in combination with radiotherapy and surgical resection. While the list of targeted therapeutics for cancer is growing, the discovery of such drugs in the standard fashion is still very challenging and typically necessitates some knowledge of a biological target that is different in the cancer cell relative to normal cells (mutated oncogenic drivers or fusion proteins from a translocation). As such, there is a pressing need for new strategies for identification of novel targeted anticancer compounds. The current landscape of compound screening libraries used in drug discovery campaigns is biased towards predominantly flat sp2-hybridized scaffolds, due in part to the ease of synthesis, modularity, and robust reaction toolkit associated with aromatic compounds, and such compounds are generally well matched to the special geometry of kinase binding pockets. Most targeted anti-cancer therapies target kinases, however, compounds with different shapes might be expected to engage different biological targets. Further, there is some evidence that compounds with a higher fraction of sp3-hybridized carbons (Fsp3) are more likely to advance through the various stages of drug discovery. In this vein many creative strategies for generation of complex, natural-product-like compounds have been developed. In the CtD strategy, the ring systems of accessible natural products are modified to generate diverse, structurally complex, value-added compounds. Notable examples of 1 500.151WO1 UIUC2023-116-02(PCT) scaffolds that have been the subjects of CtD campaigns include gibberellic acid, adrenosterone, quinine, abietic acid, pleuromutilin, sinomenine, lycorine, limonin, yohimbine, haemanthamine, and griesofulvin. CtD compounds have led to notable biological discoveries, including as the pro- ferroptotic pleuromutilin derivative ferroptocide, the eNTRy rules and PASSage guidelines to facilitate penetrance of gram-negative bacteria, and guidelines to engineer out P-gp efflux at the blood-brain barrier. Seminal studies by the Stockwell group (Cell Chem. Biol.2016, 23, 225-235) demonstrated that ferroptosis inducers displayed particularly high cell line selectivity when screened in culture against the NCI-60 panel, a set of 60 cancer cell lines representing a wide range of cancer types and oncogenes. Ferroptosis is a recently discovered mode of cell death induced by iron-mediated generation of lipid hydroperoxides. Given that the high oxidative burden in cancer cells has led to suppression of ferroptosis in a wide range of tumors, ferroptosis induction has garnered significant attention as a potential target pathway for novel therapeutic development. Many recently developed ferroptosis inducers act through one of two mechanisms. The first is inhibition of system XC-, a protein complex that transports cysteine into the cell and thereby begins the glutathione synthesis pathway. The second is inhibition of glutathione peroxidase 4 (GPX4), which uses glutathione to reduce the phospholipid hydroperoxides generated in ferroptosis to the corresponding alcohols. Interestingly, GPX4 inhibitors displayed greater cell line selectivity than system XC- inhibitors when screened against the NCI-60 panel. Over 100 types of cancers with a wide range of etiologies affect humans. Accordingly, there is a need for new therapies that target cancers selectively. SUMMARY This technology provides the synthesis and screening of steviokine and related derivatives in various cancer cell lines. Accordingly, this disclosure provides a compound of Formula I: or a salt thereof; wherein G1is CH2, CHORa, or C=O; G2is C=CH2, C=O, CHORb, CHN(Rc)2, C(CH2O)–, –O(C=O)–, or C(ORa)CH2ORa; each Rais independently H, –(C1-C6)alkyl, or –(C=O)(C1-C6)alkyl; each Rbis independently H, –(C1-C6)alkyl, –(C=O)(C1-C6)alkyl, or –(C=O)C ^CH; each Rcis independently H, –(C1-C6)alkyl, or –CH2C ^CH; 2 500.151WO1 UIUC2023-116-02(PCT) J1, J2, and J3are each independently H or ORa; R1is –CH2X1(C=O)R3or –CO2(C1-C6)alkyl, wherein X1is NR4or O; R2is ORa, CH3, CH2ORb, or CHO; R3is –C ^CH, –C ^CCH3, –C ^C-Si(CH3)3, –CH=CH2, –SO2CH=CH2, –(C1-C6)alkyl, or CH2X2wherein X2is halo; and R4is H or –(C1-C6)alkyl. This disclosure also provides a method for treating a cancer comprising administering to a subject having the cancer a therapeutically effective amount of a compound or composition of a compound of Formula I, wherein the cancer is thereby treated. The invention provides novel compounds of Formula I and Formula II, intermediates for the synthesis of compounds of Formula I and Formula II, as well as methods of preparing compounds of Formula I and II. The invention also provides compounds of Formula I and II that are useful as intermediates for the synthesis of other useful compounds. The invention provides for the use of compounds of Formula I and Formula II for the manufacture of medicaments useful for the treatment of bacterial infections in a mammal, such as a human. The invention provides for the use of the compositions described herein for use in medical therapy. The medical therapy can be treating cancer, for example, blood cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, or colon cancer. The invention also provides for the use of a composition as described herein for the manufacture of a medicament to treat a disease in a mammal, for example, cancer in a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention. Figure 1. CtD transformations on Isosteviol and Steviol. Figure 2A-B. (A) IC50of Steviokine against 25 human cancer cell lines. (B) Cytoprotectant screen. Figure 3. Flow cytometry confirming generation of lipid ROS. Figure 4. Outline of target identification experiments. Figure 5A-B. (A) Proteomic screen results. (B) DepMap knockdown data. The reliance on cell viability with GPX4 knockout agrees with the potency of Steviokine. 3 500.151WO1 UIUC2023-116-02(PCT) Figure 6A-E. Confocal experiments using (A) Mito Tracker, (B) ER tracker, and (C) GPX4 antibody; (D) siRNA and shRNA knockdown correlations from PRISM screening; (E) Dose- dependent GPX4 pulldown. Figure 7. (A) Competition experiments with other known GPX4 inhibitors. (B) CETSA experiments on GPX4 using Steviokine, RSL3, and ML210. Figure 8. Graph of steviokine concentration versus time.10 mg / kg, 3 female C57BL / 6 mice per time point. Formulation : 2 mg / mL in 50% DMSO, 50% PEG400. IP administration. Figure 9A-E. Screening of top compounds against an expanded cell line panel. (A) Steviokine. (B) Steviokine acetate. (C) Hydroxysteviokine. (D) Isosteviokine. (E) Isosteviokine alkyne.72 h, Alamar blue cell viability assay; 50 μM raptinal as dead control. Error is SEM. Figure 10. Cytoprotectant screen to determine mode of death. Steviokine appears to induce ferroptosis in OPM-2 and HepG2 cells. OPM-2 cells were pretreated with protectant for 2 h, then incubated with Steviokine for 4.5 h. DETAILED DESCRIPTION Steviol is a diterpene natural product that is isolated from the plant Stevia rebaudiana. Steviol is biosynthesized in the plant as steviol glycosides. Steviol glycosides were discovered to have therapeutic effects against several diseases including cancer. Studies have shown that steviol glycosides do not cause acute and subacute toxicity. The biological and pharmacological properties of derivatives of steviol aglycon could provide compounds useful for the treatment of human diseases. Disclosed herein is the discovery of Steviokine and related compounds: , N-(((4R,6aR,9S,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9- methanocyclohepta[a]naphthalen-4-yl)methyl)propiolamide (Steviokine). 4 500.151WO1 UIUC2023-116-02(PCT) Definitions. The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley’s Condensed Chemical Dictionary 14thEdition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001. References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described. The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted. As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect. 5 500.151WO1 UIUC2023-116-02(PCT) The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph. As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub- ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, … 9, 10. It also means 1.0, 1.1, 1.2. 1.3, …, 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on. If the variable disclosed is a number less than “number10”, it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above. Similarly, if the variable disclosed is a number greater than “number10”, it implies a continuous range that includes whole numbers and 6 500.151WO1 UIUC2023-116-02(PCT) fractional numbers greater than number10. These ranges can be modified by the term “about”, whose meaning has been described above. One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation. The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect. Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of 7 500.151WO1 UIUC2023-116-02(PCT) supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment). The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate. As used herein, "subject" or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, the patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods provided herein, the mammal is a human. As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compound can be administered by any appropriate route that results in delivery to a desired location in the subject. The compound and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs. The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting. The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For 8 500.151WO1 UIUC2023-116-02(PCT) example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%. Wherever the term “comprising” is used herein, options are contemplated wherein the terms “consisting of” or “consisting essentially of” are used instead. As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the aspect element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. This disclosure provides methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques described herein, optionally in combination with standard techniques of organic synthesis. Many techniques such as etherification and esterification are well known in the art. However, many of these techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol.1, Ian T. Harrison and Shuyen Harrison, 1971; Vol.2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.3, Louis S. Hegedus and Leroy Wade, 1977; Vol.4, Leroy G. Wade, Jr., 1980; Vol.5, Leroy G. Wade, Jr., 1984; and Vol.6; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., by M. B. Smith and J. March (John Wiley & Sons, New York, 2001); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); for heterocyclic synthesis see Hermanson, Greg T., Bioconjugate Techniques, Third Edition, Academic Press, 2013. The formulas and compounds described herein can be modified using protecting groups. Suitable amino and carboxy protecting groups are known to those skilled in the art (see for example, Protecting Groups in Organic Synthesis, Second Edition, Greene, T. W., and Wutz, P. G. M., John Wiley & Sons, New York, and references cited therein; Philip J. Kocienski; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), and references cited therein); and Comprehensive Organic Transformations, Larock, R. C., Second Edition, John Wiley & Sons, New York (1999), and referenced cited therein. The term "halo" or "halide" refers to fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine. 9 500.151WO1 UIUC2023-116-02(PCT) The term "alkyl" refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms; or for example, a range between 1-20 carbon atoms, such as 2-6, 3-6, 2-8, or 3-8 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec- butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include an alkenyl group or an alkynyl group. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene). An alkylene is an alkyl group having two free valences at a carbon atom or two different carbon atoms of a carbon chain. Similarly, alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms, or an alkenylene can have the two free valences on the same carbon. The term "cycloalkyl" refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more sites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like. The term “heteroatom” refers to any atom in the periodic table that is not carbon or hydrogen. Typically, a heteroatom is O, S, N, P. The heteroatom may also be a halogen, metal or metalloid. The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3- to 10-membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group. 10 500.151WO1 UIUC2023-116-02(PCT) The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted with a substituent described below. For example, a phenyl moiety or group may be substituted with one or more substituents RXwhere RXis at the ortho-, meta-, or para-position, and X is an integer variable of 1 to 5. The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted". Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5- membered rings, two 6-membered rings, or a 5-membered ring fused to a 6-membered ring. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H- quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, ^-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C1-C6)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. As used herein, the term "substituted" or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that 11 500.151WO1 UIUC2023-116-02(PCT) the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfinyl, and alkylsulfonyl. Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano. Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', OC(O)N(R')2, CN, CF3, OCF3, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', SO2R', SO2N(R')2, SO3R', C(O)R', C(O)C(O)R', C(O)CH2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, C(S)N(R')2, (CH2)0-2NHC(O)R', N(R')N(R')C(O)R', N(R')N(R')C(O)OR', N(R')N(R')CON(R')2, N(R')SO2R', N(R')SO2N(R')2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')2, N(R')C(S)N(R')2, N(COR')COR', N(OR')R', C(=NH)N(R')2, C(O)N(OR')R', or C(=NOR')R' wherein R’ can be hydrogen or a carbon-based moiety (e.g., (C1-C6)alkyl), and wherein the carbon-based moiety can itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is divalent, such as O, it is bonded to the atom it is substituting by a double bond; for example, a carbon atom substituted with O forms a carbonyl group, C=O. Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is 12 500.151WO1 UIUC2023-116-02(PCT) referred to as a racemic mixture or a racemate (defined below), which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “IC50” is generally defined as the concentration required to inhibit a specific biological or biochemical function by half, or to kill 50% of the cells in a designated time period, typically 24 hours. Embodiments of the Technology. wherein G1is CH2, CHORa, or C=O; G2is C=CH2, C=O, CHORb, CHN(Rc)2, C(CH2O)–, –O(C=O)–, or C(ORa)CH2ORa; each Rais independently H, –(C1-C6)alkyl, or –(C=O)(C1-C6)alkyl; each Rbis independently H, –(C1-C6)alkyl, –(C=O)(C1-C6)alkyl, or –(C=O)C ^CH; each Rcis independently H, –(C1-C6)alkyl, or –CH2C ^CH; J1, J2, and J3are each independently H or ORa; R1is –CH2X1(C=O)R3or –CO2(C1-C6)alkyl, wherein X1is NR4or O; alkyl, or2 CH2X wherein X2is halo; and R4is H or –(C1-C6)alkyl. In some embodiments, G1is CH2 or CHORa. In some embodiments, G2is C=CH2, C=O, or CHN(Rc)2. In some embodiments, J1, J2, and J3are each H. In some embodiments, R1is –CH2X1(C=O)R3and R3is –C ^CH. In some embodiments, R1is –CH2NH(C=O)C ^CH. In some embodiments, R2is ORaor CH3. In some embodiments, the compound is represented by Formula II: wherein the substituents for Formula II are defined by Formula I and X3is CH2or O. 13 500.151WO1 UIUC2023-116-02(PCT) In some embodiments, X1id NH. In some embodiments, R3is –C ^CH. In some 14 500.151WO1 UIUC2023-116-02(PCT) In some other embodiments, the compound is: a salt thereof. In yet other embodiments, the compound is: 15 500.151WO1 UIUC2023-116-02(PCT) a salt thereof. This disclosure also provides a composition comprising a compound of Formula I or II and a pharmaceutically acceptable diluent or carrier. In various embodiments, the composition comprises only a single diastereomer of the compound to an extent of at least 95%, such that if several stereoisomers of the same compound exists in the composition, then one stereoisomer is predominant to the extent of 95%, 96%, 97%, 98%, 99%, or more. Additionally, this disclosure provides a method of treating a cancer comprising administering to a subject having the cancer a therapeutically effective amount of a compound or composition of Formula I or II, wherein the cancer is thereby treated. In some embodiments, the cancer is one or more of blood cancer, brain cancer, breast cancer, bone cancer, cervical cancer, colon cancer, esophageal adenocarcinoma, glioblastoma, head and neck cancer, hematopoietic cancer, kidney cancer, leukemia, liver cancer such as hepatocellular carcinoma, lung cancer, lymphoma, melanoma, multiple myeloma, muscle cancer, oral cavity cancer, ovarian cancer, pancreatic cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer, rhabdomyosarcoma, sarcoma, skin cancer, splenic cancer bladder cancer, thyroid cancer, urothelial cancer, urinary bladder cancer, and uterine cancer. In certain embodiments, the cancer is multiple myeloma or leukemia. In various other embodiments, the cancer is kidney cancer, liver cancer, or prostate cancer. Identification of a Covalent GPX4 Inhibitor and Selective Anticancer Compound from a Collection of Complex-and-Diverse Compounds from Steviol. Here we detail the synthesis of a collection of >100 complex and diverse compounds created from the triterpenoidnatural product stevioside (1). Screening led to the discovery of the novel compound steviokine (23), which displayed promising and selective anticancer activity against a panel of cancer cells in culture. Proteomic and other experiments reveal GPX4 as the target of steviokine. Steviokine is unique among other known GPX4 inhibitors in that it is predominantly sp3hybridized and appears to bind to a novel cysteine of GPX4, suggesting the potential of other globular scaffolds to achieve comparable activity and selectivity when primed with the propiolamide warhead. We also examine the metabolic liabilities of the propiolamide warhead. 16 500.151WO1 UIUC2023-116-02(PCT) Results. Synthesis of complex-and-diverse compounds from Stevioside. Stevioside (1) (Fig.1) is a readily available natural product ($0.40 / g) isolated from the plant Stevia rebaudiana and is the major component of the sweetener stevia. Stevioside is neither mutagenic nor carcinogenic, and glycoside hydrolysis can lead to liberation of the triterpenoid scaffold for further modification. Specifically, glycoside cleavage under acidic conditions results in a Wagner-Meerwein rearrangement to generate Isosteviol (2). Under oxidative and basic conditions, the glycosidic bonds of Stevioside can be cleaved to generate the triterpenoid scaffold Steviol (3). Steviol glycosides as a whole display a range of promising biological properties, including anti-inflammatory effects, anticancer activity, antioxidant properties, anti-diabetic effects, anti-obesity effects, and antihypertensive properties, to name a few. Together, Steviol and Isosteviol serve as excellent scaffolds for further derivatization given their high Fsp3and the low price and promising pharmacological profile of the parent compound. Previous work on these scaffolds has centered around modification of the D ring, peripheral functionalization at the alcohol and / or carboxylic acid, and C-H activation. Fig.1 highlights the key novel transformations carried out on Isosteviol and Steviol. The majority of transformations on Isosteviol rely either on cleavage of the A-ring or ring fusion. Specifically, ring-expanded product 4 and ring-contracted product 5 are both readily prepared from Isosteviol in six steps through oxidative cleavage of the A-ring followed by reformation of the ring. Interestingly, treatment of Isosteviol with Tl(NO3)3(TTN) in AcOH results in cyclopropanation, giving intermediate 6. On exposure to HNO3and AcOH, this intermediate readily rearranges to the tetracyclic enone 7, which can then undergo ring cleavage to give 8, Baeyer-Villiger ring expansion to give 9 and 10, or Beckmann rearrangement to give 11 and 12. TTN-mediated cyclopropanation can also easily be combined with other modifications, such as A-ring cleavage in 13 and sulfonamide ring fusion 14, discovered by the White group (Nat. Chem.2015, 7, 987-994). This sulfonamide moiety was also subjected to Baeyer-Villiger ring expansion to afford 15. The majority of transformations carried out on Steviol rely on modification of the D-ring, either driven by alkene migration or ozonolytic cleavage. The former transformation allowed for the synthesis of ring-fused and ring-expanded derivative 16 in 6 steps, while the latter approach resulted in formation of the established intermediate 17. This intermediate then allowed for several ring distortions, such as C-ring contraction (18), ring fusion (19), ring rearrangement (20), and ring expansion (21 and 22). In addition to D-ring modifications, transformations were carried out at the peripheral carboxylate to install an electrophilic warhead, as evidenced by 23, hereafter referred to as Steviokine. Screening the collection for anticancer activity. Given the growing interest in electrophilic compounds as anticancer therapies, Steviokine was assessed against a panel of 25 human cancer cell lines in culture representing a wide range of tumor types in 72 hour IC50 experiments. Excitingly, 17 500.151WO1 UIUC2023-116-02(PCT) Steviokine displayed low double digit nanomolar activity against cell lines such as Caki-1 and HepG2, and over 20 micromolar activity against cell lines such as A549 and IU-TAB-1. The time to cell death was determined through a wash-out IC50assay with compound-containing media removed at 1, 2, 4, 6, 8, 24, and 48 hours in HepG2 and HCT116 cells. In both cell lines, the 72-hour IC50 of Steviokine was reached in 48 hours. The safety of Steviokine was explored through a hemolysis assay. Excitingly, Steviokine is non-hemolytic up to 200 μM. Anticancer mode-of-action of steviokine. To determine the mode of death induced by Steviokine, HepG2 cells were pretreated with a range of established cytoprotectants, followed by administration of DMSO or Steviokine for 3.5 hours. These cells were then stained with Annexin V- FITC and PI, and the live populations of the DMSO- and Steviokine-treated cells were measured by flow cytometry (Fig 2B). Trolox, tiron, ferrostatin-1, and deferoxamine all showed essentially complete protection against Steviokine-induced cell death in this experiment, suggesting that Steviokine induces ferroptosis in HepG2 cells. To further explore ferroptotic induction, lipid ROS accumulation in Steviokine-treated HepG2 cells was assessed. For this experiment HepG2 cells were treated with DMSO, Steviokine, or the ferroptosis inducer RSL3, followed by 20-minute incubation with C11-BODIPY (581 / 591), whose excitation / emission wavelengths shift from 581 / 591 nm to 488 / 510 nm on oxidation by lipid peroxides. These cells were then subjected to flow cytometry, where cells were irradiated with a 488 nm laser and emission at 510-540 nm was measured (Fig 3). As expected, the Steviokine-treated samples display a marked increase in fluorescence intensity at 510-540 nm typically associated with lipid ROS generation. Structure-activity relationship of steviokine. With its excellent cell line selectivity, nineteen derivatives of Steviokine were synthesized to explore its structure-activity relationship (Chart 1). Five different D-ring derivatives were synthesized by acetylation of the alcohol on the bridgehead of the C and D ring, epoxidation of the olefin, allylic oxidation by the Sharpless oxidation, 27, an α, β unsaturated ketone through DMP oxidation on 27. The final D-ring derivative is an alkene rearrangement on the D-ring to afford an internal olefin and terminal methyl group. To explore the potency of the propiolic group, seven different derivatives were synthesized with various placements and linkages, either N- or O- linkages, of the electrophile were synthesized. The isosteviol analog of Steviokine was synthesized by a BF3 promoted rearrangement, 28. The ester analog of Steviokine was synthesized from Steviol by an LAH reduction and DCC coupling to afford the propiolic warhead. In an analogous synthesis, the ester derivative with the C and D ring rearrangement was made. A NaBH4reduction on Isosteviol afforded the D-ring alcohol. Following methyl esterification and DCC coupling with propiolic acid afforded the coupled product. The amide analog, 26 was synthesized by oxime formation, TiCl3reduction and electrophile coupling. Another Wagner- Meerwein rearrangement of the C and D ring was performed with TFA on the methyl ester of Isosteviol to afford the D ring ketone and primary alcohol off of the bridgehead position. A DCC 18 500.151WO1 UIUC2023-116-02(PCT) coupling with propiolic acid gave the coupled product. To further investigate the selectivity of the warhead, as explored by the Schreiber group (Bioorg. Med. Chem. Let.2020, 30, 127538), the subsequent was made by coupling with the TMS protected propiolic acid. Given the facial rearrangement of Steviol to Isosteviol, seven derivatives were synthesized. Four were synthesized from 28 including oxime formation on the D-ring, a TiCl3 mediated reduction to yield an aminated derivative 31, NaBH4 reduction to furnish the D-ring alcohol, and Bayer-Villager ring expansion to expand the D-ring 29. Steviokine was subjected to a TFA-mediated Wagner Meerwein rearrangement to produce 30, which was further oxidized to the aldehyde. A reductive amination on 28 with propargyl amine yielded 32, herein referred to as Probe. These steviologs were tested for their anti- proliferative activity in a panel of cell lines. Additionally, the precursor compounds to Steviokine and the electrophilic isosteviol derivative 28 were tested against a small panel of cell lines to determine the requirements for reactivity. Chart 1. SAR of Steviokine. Proteomics experiments and target identification. After synthesis of Probe, we sought to identify the biological target of Steviokine through target identification experiments outlined in Fig 4. For the proteomic experiments, eight million HepG2 cells were pretreated with DMSO or 50 μM Steviokine for 30 minutes, followed by incubation with 20 μM Probe for 70 minutes. High concentrations were required to ensure that sufficient protein would be eluted in the pulldown. After 19 500.151WO1 UIUC2023-116-02(PCT) trypsin harvesting, the cells were lysed and protein concentrations were normalized to 2 mg / mL. Biotin-N3was attached to the alkyne of Probe using click chemistry, and pulldown was carried out using neutravidin beads. Fig 5A shows the results of the proteomic screen, comparing the proteins isolated from the Steviokine-pretreated sample (left) to those isolated from the Probe-treated sample (right). MS analysis of the treated protein solutions revealed that 15 proteins were highly abundant in the Probe- treated samples compared to the Steviokine-treated samples, indicating that Steviokine binds to these proteins. Knockdown dependence data made publicly available on the DepMap (Cell 2017, 170, 564- 576.e16) for each of these proteins was compared for all available cell lines in the panel from Fig 2A. Gene dependence values ≤ -0.5 indicate significant cell death induced by knockdown of a given gene in the cell line in question, meaning that for the biological target of Steviokine, gene dependence should correlate with the IC50 data collected from cell culture. As illustrated in Fig 5B, only GPX4 knockdown results in a comparable cell death profile compared to Steviokine. To better understand the subcellular localization of Steviokine, confocal microscopy experiments were run with the Probe. HepG2 cells were seeded at 300,000 cells per well and incubated with 10 μM Probe or DMSO for 3 hours. For samples labeling the mitochondria, MitoTracker Red was incubated for 30 minutes before fixing and permeabilizing the cells. A click reaction with the fluorescent dye Az488 was performed to visualize the Probe. The GPX4 samples were labeled using a GPX4 antibody and fluorescent secondary antibody. An hour before imaging, ER tracker and / or DAPI were incubated with the cells. The cells were imaged at 63 times magnification. The Probe showed excellent overlap with ER Tracker (Fig 6A) and good overlap with MitoTracker (Fig 6B). Further, as evidenced with other GPX4 inhibitors, the Probe is localizing around GPX4 (Fig 6C). The cell line selectivity and mode-of-action of Steviokine was further explored through the Broad Institute’s PRISM program, with assessment against roughly 900 human cancer cell lines (Nat. Biotechnol.2016, 34, 419-423). The cell death data against these cell lines were then correlated with publicly available siRNA and shRNA knockdown data stored on the DepMap (Fig 6D). In each case, GPX4 knockdown shows the most significant correlation with activity displayed in cell culture, further validating GPX4 as the biological target of Steviokine. Of note, the other three high- correlation proteins in siRNA knockdown (SEPHS2, EEFSEC, and SEPSECS) are all involved in selenocysteine synthesis and / or metabolism; as these proteins are all upstream in the GPX4 synthesis and expression pathway, they display similar knockdown profiles to GPX4. Given that all three routes displayed in Fig 4 indicated that Steviokine is likely a GPX4 inhibitor, dose-dependent pulldown experiments were carried out on GPX4. As with the proteomic experiments, five million HepG2 cells were treated with Probe at various concentrations for two hours, after which the cells were harvested and lysed. Protein concentration was normalized to 1 20 500.151WO1 UIUC2023-116-02(PCT) mg / sample for each concentration, followed by click reaction with biotin-N3and subsequent pulldown with neutravidin beads. Western blot of the pulldown eluate is shown in Fig 6E, along with Western blots of the inputs of each sample normalized to 10 μg / lane. The GPX4 band intensity in the pulldown eluate is proportional to the probe concentration, further supporting the above target identification experiments. With the biological target of Steviokine established, we sought to compare Steviokine to other established GPX4 inhibitors, whose structures are shown in Chart 2. FIN56 is an established GPX4 degrader, rather than a covalent inhibitor, and was included as an additional negative control in the competition experiments outlined below. To begin, competition experiments were carried out using GPX4, wherein five million HepG2 cells were pretreated with DMSO or 625 nM GPX4 inhibitor for one hour followed by treatment with 156 nM Probe for two hours. Pulldown and Western blot were carried out, as shown in Fig 7A. The propiolamide-containing PACMA31 displays full competition with the Probe, as evidenced by the lack of any banding post-pulldown. Steviokine itself and RSL3 display modest competition, while ML162 and ML210 minimally compete with the Probe. Cellular thermal shift assays (CETSA) were then carried out to determine the degree to which Steviokine stabilizes GPX4 on binding (Fig 7B). HepG2 cells seeded at 14 million cells / condition were treated with DMSO, 10 μM Steviokine, 10 μM RSL3, or 10 μM ML210 for one hour. The cells were harvested and aliquoted into one million cell portions, which were heated to 40-70 °C in three- degree intervals. Western blots were then run on each sample for GPX4. The blots shown in Fig 7B are consistent with the literature CETSA experiments for RSL3 and ML210; the former is known to destabilize GPX4 on binding, while the latter is known to stabilize it. Interestingly, Steviokine does not induce any change in thermal stability of GPX4. Chart 2. Established GPX4 inhibitors. 21 500.151WO1 UIUC2023-116-02(PCT) The metabolism of drug-like molecules is crucial to their clinical success. Thus, Steviokine was tested in a mouse liver microsome assay to determine its metabolic liabilities.50 μM Steviokine was incubated with 1 mg / mL mouse liver microsomes for two hours, with samples taken at 0, 1, and 2 hours and analyzed by LC-MS / MS. This assay was repeated for Steviol, steviol amine, propenamide, and cyme. To determine the metabolites of Steviokine, an LC-MS assay was conducted using the same procedure as above with samples taken at 0 and 1 hours. The standard for this assay was 25 μM Steviokine and 25 μM 27. New metabolites were identified by both a new peak in the LC-MS trace and a decrease in the area under the Steviokine peak. The same area under the curve was observed at 0 hours. However, after 1 hour, the Steviokine peak decreased and a new peak was formed. The peak showed a mass of 390, or M+34, indicating that Steviokine was likely oxidized. A similar microsome experiment was conducted with three precursor molecules, that showed marketed stability compared to Steviokine indicating that the metabolite is likely occurring with the propiolamide. Oxidative metabolism of drugs mainly occurs through the cytochrome P450 enzyme, CYP3A4. Ritonavir, a known CYP3A4 inhibitor, was co-dosed with 50 μM Steviokine at 20 μM and 200 μM to determine if Steviokine is metabolized by CYP3A4. Instead of 0.1% of Steviokine remaining after 2 hours, 47% remained when co-dosed with 200 μM ritonavir indicating that CYP3A4 is responsible for metabolism of Steviokine. Discussion. Structure Activity Relationships. The location of the electrophile around the scaffold changes the potency of the compound. The rearranged C and D ring of the isosteviol scaffold provides an almost 4-fold increase in activity against the most suspectable cell line compared to the parent compound, Steviokine. The D-ring amide compound further increases this potency while maintaining excellent (over 530-fold) selectivity. In general, having the electrophile on the D-ring increases potency, have more activity in unsusceptible cell lines than Steviokine. Unsurprisingly, when there are two electrophilic moieties present in the same molecule, potency is increased and selectivity is ablated. Changing the location of the olefin and to an internal olefin decreases potency, while expanding the D-ring increases the potency. Further, appending a TMS group onto the warhead retains similar potency to Steviokine. When exploring modifications on the periphery of the D-ring, appending an allylic alcohol decreases the potency of the molecule but still retains over 100-fold selectivity. Similarly, appending a primary alcohol on the bridgehead decreases potency. Oxidizing to the aldehyde has similar potency to the primary alcohol. However, appending an oxime on the D-ring ablates potency. Reducing the oxime to a primary amine, regains potency similar to the parent compound. 22 500.151WO1 UIUC2023-116-02(PCT) In the non-electrophilic precursor compounds of Steviokine, limited to no activity was observed up to 100 μM in OPM2, HepG2 and HCT116. Thus, the propiolamide is required for the anti-proliferative activity of Steviokine. When considering the ester or the amide linkage, the ester containing compounds showed increased reactivity in the panel of non-suspectable cell lines. This is not surprising given the known liability of esters in physiological systems due to the presence of esterases. The amide linked warhead, however, shows excellent cell line selectivity. To explore this change in activity between HepG2 and HCT116 cells, the cytoprotectant, ferrostatin-1, was used to protect the cells from the ferroptotic cell death. Protection was only exhibited for the ester and amide analog in HepG2 cells, but not in HCT116 cells. HCT116 has a lower reliance on GPX4 than HepG2, and the antiproliferative activity in HCT116 is occurring through a mechanism independent of ferroptosis. Metabolic Liabilities of the Propiolamide. There are no FDA approved drugs that contain the propiolamide warhead. Beyond the inherent reactivity of this Micheal acceptor, to our knowledge, there has not been much work on the metabolic liabilities of the propiolamide. In a glutathione binding assay, the half-life is 0.40 hours related to the butanamide, which is over 100 times less reactive with a half-life of 41 hours. Given the excellent selectivity observed with Steviokine, we began to explore the drug-like properties of this molecule with an emphasis on the electrophilic warhead. In initial PK studies, Steviokine is cleared in 2 hours. This was corroborated with results from a microsomal stability assay. Only 0.1% of Steviokine remained after 2 hours. To understand which part of the molecule was the cause of these metabolic liabilities, three different precursor compounds, including Steviol, as well as the simple propiolamide, were also tested for their microsomal stability. For each of the three precursor compounds, more than 75% of each precursor compound remained after 2 hours. There was an increase in metabolism of the simple propiolamide compared to the stevioside-based molecules. Thus, the terpenoid backbone is likely not the cause of the metabolitic liabiltites, but rather the propiolamide warhead. With the knowledge that the warhead is likely the reason for the metabolic instability, we set out to identify the metabolite. The LC-MS trace after 1 hour, showed a new peak corresponding to an M+1 of 390 m / z. This increase in 34 mass units corresponds to a dihydroxylation that likely tautomerizes into a carboxylic acid. This metabolite was identified by LC-MS and LC-MS / MS. The amount of metabolite was quantified at 0, 1, and 2 hours where the amount of metabolite steadily increased. When testing Steviokine co-dosed with the known CYP3A4 inhibitor, ritonavir, in a comparable mouse liver microsome assay, the metabolic liabilities of the compound decreased. Dosing ritonavir at 40% of the concentration of Steviokine, metabolic protection was observed with 21% and 4.3% remaining after 1 and 2 hours respectively. A dramatic increase in stability towards the microsomes was observed when ritonavir was dosed at four times the concentration of Steviokine, 23 500.151WO1 UIUC2023-116-02(PCT) with 67% and 47% remaining at 1 and 2 hours. Thus, some of the metabolic liabilities are due to metabolism by CYP3A4. Conclusion. Steviokine is a novel GPX4 inhibitor that is highly sp3hybridized that target _ cysteine of GPX4, which is different than known GPX4 inhibitors, such as RSL3 and ML210. While the propiolamide warhead is liable to metabolism, the highly electrophilic nature of this electrophilic moiety does not ablate cell line selectivity. If the metabolic liabilities can be properly masked, then the propiolamide is a reasonable covalent warhead for drug development. Overall, this work shows promise for more three-dimensional electrophilic molecules that can be used for anti-cancer treatments. Pharmaceutical Formulations. The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and ^-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods. The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes. The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations 24 500.151WO1 UIUC2023-116-02(PCT) typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained. The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms. Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and / or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, 25 500.151WO1 UIUC2023-116-02(PCT) sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and / or gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution. For topical administration, compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer the active agent to the skin as a composition or formulation, for example, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid, a gel, or the like. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol / glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S. Patent Nos.4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.). Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition. Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician. 26 500.151WO1 UIUC2023-116-02(PCT) In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg / kg, e.g., from about 10 to about 75 mg / kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg / kg / day, most preferably in the range of 15 to 60 mg / kg / day. The compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form. The compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg / m2, conveniently 10 to 750 mg / m2, most conveniently, 50 to 500 mg / m2of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations, such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The invention provides therapeutic methods of treating cancer in a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, and the like. Cancer refers to any various type of malignant neoplasm, for example, colon cancer, breast cancer, melanoma and leukemia, and in general is characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis. The ability of a compound of the invention to treat cancer may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of tumor cell kill, and the biological significance of the use of transplantable tumor screens are known. The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention. 27 500.151WO1 UIUC2023-116-02(PCT) EXAMPLES Example 1. Synthetic methods. Scheme 1. Synthesis of Steviokine. Synthetic Procedures: Procedure 1: In a 2-L 3-neck round bottom flask, stevioside hydrate 1 (100 g, 124 mmol, 1.0 eq) was stirred in DI water (1.25 L) at ambient temperature until dissolved. Powdered NaIO4 (150 g, 701 mmol, 5.65 eq) was slowly added and the reaction was stirred at RT for 24 h. The resulting white slurry was cooled to 0 °C and KOH (383 g, 6.82 mol, 55.0 eq) was added in 6 portions over 1 h. The mixture was warmed to RT (~22oC) over 30 min, a reflux condenser was fitted to the flask, and the temperature was slowly increased to reflux. After 24 h, the reaction was allowed to cool to RT. The reaction was then cooled to 0 °C and carefully acidified with AcOH to pH ~ 4. The mixture was extracted with EtOAc until LCMS indicated no product remaining in the aqueous layer. The combined organic extracts were washed with a minimal amount of saturated aqueous Na2S2O3 to decolorize remaining iodine, washed with brine, dried over anhydrous MgSO4, filtered, and 28 500.151WO1 UIUC2023-116-02(PCT) concentrated in vacuo to give a yellow solid. Recrystallization from MeOH afforded steviol (2) in 40% yield (15.8 g, 49.6 mmol) as a white solid. Procedure 2: In a 3-neck round bottom flask under nitrogen, steviol (2) (1.0 g, 3.14 mmol, 1.0 eq) and hydroxybenzotriazole monohydrate (HOBt) (595 mg, 4.4 mmol, 1.4 eq) were dissolved in anhydrous THF (32.0 mL). The mixture stirred for 10 min, then EDCI ^HCl (843 mg, 4.4 mmol, 1.4 eq) was added. The resulting mixture was stirred at room temperature overnight. After 18 h, aqueous ammonium hydroxide (NH4OH) [7.85 mL, (2.5 mL per mmol steviol)] was added dropwise and let stir at RT. After 1 h, EDCI ^HCl (843 mg, 4.4 mmol, 1.4 eq) was added and the reaction was heated to 40 ºC for 20 h. The reaction was then cooled to 0 °C and 1 M aqueous HCl (49 mL) was added dropwise. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3and brine, dried over anhydrous MgSO4, and concentrated in vacuo to afforded amide 3 in 88% yield (870 mg, 2.74 mmol) as an off-white solid which was taken to the next step without further purification. Procedure 3: In a 50 mL round bottom flask under nitrogen, amide 3 (1.10 g, 3.45 mmol, 1.0 eq) and DMAP (42 mg, 0.35 mmol, 0.10 eq) were dissolved in pyridine (10 mL). The solution was cooled to 0 °C and TBSOTf (2.00 g, 7.60 mmol, 2.2 eq) was added dropwise. The reaction was warmed to RT and stirred overnight, then quenched by the addition of saturated aqueous NH4Cl and diluted with dichloromethane. The mixture was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated. The crude product was purified by column chromatography (70:30 hexanes:EtOAc) to afford 4 as a white solid (1.27 g, 2.92 mmol) in 85% yield. 29 500.151WO1 UIUC2023-116-02(PCT) Procedure 4: A solution of amide 4 (1.25 g, 2.90 mmol, 1.0 eq) in anhydrous THF (60 mL) under nitrogen was cooled to 0°C. Lithium aluminum hydride (330 mg, 8.70 mmol, 3.0 eq) was slowly added in 3 portions, and after stirring for 20 mins at 0 °C the flask was equipped with a reflux condenser. The reaction was then heated to 75 ºC and refluxed overnight. After 18 h, the reaction was cooled to 0 °C and quenched according to the Fieser workup. The aqueous layer was filtered through celite and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford crude amine 5 (1.13 g, 2.71 mmol) in 93% yield as a colorless oil which was taken to the next step without further purification. Procedure 5: In a 100 mL round bottom flask under nitrogen, amine 5 (1.79 g, 4.28 mmol, 1.0 eq) was dissolved in DCM (21 mL) and cooled to 0 °C. Propiolic acid (0.35 mL, 5.6 mmol, 1.3 eq) was added dropwise, followed by dropwise addition of a solution of DCC (1.18 g, 5.6 mmol, 1.3 3q) and DMAP (81 mg, 0.66 mmol, 0.15 eq) in DCM (16 mL). After 2.5 hours, the reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The mixture was extracted with EtOAc. The combined organic extracts were washed repeatedly with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography (95:5 to 80:20 hexanes:EtOAc) to afford amide 6 ( 1.12 g, 2.39 mmol) in 54% yield as a yellow solid. 30 500.151WO1 UIUC2023-116-02(PCT) Procedure 6: In an oven-dried 5 mL round bottom flask under nitrogen, amide 6 (130 mg, 0.28 mmol, 1.0 eq) was dissolved in anhydrous acetonitrile. The solution was cooled to 0 °C and BF3^Et2O (68 µL, 0.56 mmol, 2 eq) was added dropwise. The reaction was stirred at 0 °C for 2 h, then quenched carefully by the addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude material was purified by column chromatography (90:10 to 60:40 hexanes:EtOAc (spiked with 1% MeOH)) to afford amide 7 (77 mg, 0.22 mmol) in 78% yield as a white solid. Characterization Data for Main Steviol Derivatives. A round bottom flask was charged with starting material (603 mg, 1.28 mmol), dissolved in anhydrous 2:1 DCM / MeCN (4.3 mL) and cooled to 0°C. BF3OEt2 (0.52 mL, 4.2 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 21 hours. The reaction was quenched with sat. NaHCO3and diluted with EtOAc. The organic layer was washed with sat. NaHCO3and brine, dried over sodium sulfate and dry loaded on celite. The products were purified by silica gel column chromatography with a gradient from 10:1:89 EtOAc: MeOH: Hex to 50:1:49 EtOAc: MeOH: Hex. Note: Ratio of A:B is determined by length of reaction; leaving the reaction over 1-2 days will encourage formation of product B. Product A was isolated as a white solid in 57% yield (260 mg).1H-NMR ((CD3)2SO, 500 MHz): δ 4.89 (q, 1H), 4.75 (d, 1H), 4.69 (d, 1H), 4.11 (d, 1H), 3.57 (dd, 1H), 2.80 (dd, 1H), 2.06 (m, 2H), 1.92 (dd, 1H), 1.77 (m, 1H), 1.68 (q, 2H), 1.62 (m, 1H), 1.58-1.22 (m, 9H), 1.17 (m, 1H), 1.01 (s, 3H), 0.94 (d, 1H), 0.91 (d, 1H), 0.78 (s, 3H).13C-NMR ((CD3)2SO, 125 MHz): δ 156.77, 152.53, 102.91, 79.18, 78.97, 76.17, 60.2456.81, 54.84, 47.79, 46.63, 41.19, 41.38, 40.45, 39.05, 38.25, 28.32, 18.37, 18.32. HRMS(ESI): m / z calc. for [M+H]+= 356.2590, found: 356.2589. Product b was isolated as a white solid in 23% yield (104 mg).1H-NMR (CD3Cl, 500 MHz): δ 5.74 (q, 1H), 3.67 (ddd, 1H), 2.93 (ddd, 1H), 2.72 (s, 1H), 2.58 (dd, 1H), 1.70 (dd, 1H), 1.60 (dtt, 5H), 1.50 (m, 4H), 1.30 (m, 5H), 1.15 (m, 2H), 1.06-0.93 (m, 2H), 0.91 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.81 (td, 1H).13C-NMR (CD3Cl, 125 MHz): δ 222.47, 152.17, 79.53, 73.12, 57.00, 55.57, 54.42, 48.71, 48.60, 42.36, 41.42, 39.40, 39.28, 37.60, 37.56, 37.53, 37.26, 36.38, 27.83, 20.10, 20.03, 19.88, 17.93, 15.71 HRMS(ESI): m / z calc. for [M+H]+= 356.2590, found: 356.2596. 31 500.151WO1 UIUC2023-116-02(PCT) A round bottom flask was charged with oxime (55.8mg, 0.151 mmol), NaCNBH3(32.3 mg, 0.514 mmol) and NH4OH (119.8 mg, 1.55 mmol), purged with N2, cooled to 0°C and dissolved in anhydrous MeOH (3.0 mL, 0.05M). TiCl3 (0.43 mL, 0.332 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 2.25 hours. The reaction was diluted with EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated via rotatory evaporation. The resulting crude product was purified via silica column chromatography with a gradient of DCM to 15% Ammoniacal MeOH / DCM. The product was isolated as a white solid in 32% yield (17.1 mg). 1H-NMR (CD3OD, 500 MHz): δ 3.66 (d, 1H), 2.99 (dd, 1H), 2.91 (dd, 1H), 1.77 (m, 2H), 1.68 (tdd, 4H), 1.60 (m, 4H), 1.47-1.26 (m, 7H), 1.10 (m, 2H), 1.01 (m, 1H), 0.99 (s, 3H), 0.92 (s, 3H), 0.90 (m, 1H), 0.88 (s, 3H).13C-NMR (CD3OD, 125 MHz): δ 153.78, 76.51, 59.91, 56.87, 56.40, 56.24, 43.62, 41.85, 41.80, 41.16, 41.02, 40.31, 39.14, 37.72, 37.41, 35.99, 32.62, 27.07, 23.54, 19.68, 19.54, 17.65, 14.61. HRMS(ESI): m / z calc. for [M+H]+= 357.2906, found: 357.2903. A round bottom flask was charged with the amine (124 mg, 0.372 mmol), anhydrous dichloromethane (1.9 mL) was added and cooled to 0°C. The acid (0.03 mL, 0.484 mmol) was dropwise followed by a mixture of DCC (108 mg, 0.524 mmol) and DMAP (17.1 mg, 0.140 mmol) in DCM (1.8 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with saturated NH4Cl and diluted with EtOAc. The organic layer was washed with saturated NH4Cl and brine, dried over Na2SO4and dry loaded on celite. The resulting crude product was purified via silica column chromatography with an eluent gradient of 20% EtOAc / Hex to 30% EtOAc / Hex. The product was isolated as a white solid in a 47% yield over two steps (108.5 mg). 1H-NMR (CD3Cl, 500 MHz): δ 5.79 (dd, 1H), 4.02 (m, 1H), 3.55 (d, 3H), 2.09 (dd, 1H), 1.83 (ddd, 1H), 1.73 (m, 2H), 1.62 (ddd, 2H), 1.53 (m, 6H), 1.34 (dt, 2H), 1.28 (ddd, 2H), 1.17 (qd, 1H), 1.09 (s, 3H), 1.04 (td, 1H), 0.96 (dt, 2H), 0.86 (s, 1H), 0.63 (s, 1H).13C-NMR (CD3Cl, 125 MHz): δ 178.07, 154.90, 152.21, 79.81, 73.11, 57.58, 57.00, 55.85, 55.51, 51.19, 43.75, 42.44, 41.73, 41.20, 40.76, 39.85, 38.03, 37.95, 34.03, 28.77, 24.83, 21.70, 20.69, 18.86, 13.21. HRMS(ESI): m / z calc. for [M+H]+= 386.2695, found: 386.2700. 32 500.151WO1 UIUC2023-116-02(PCT) A round bottom flask was charged with starting material (92.8 mg, 0.261 mmol) followed by the addition of anhydrous THF (4 mL) and cooled to 0°C. SeO2(26 mg, 0.235 mmol) and tBuOOH (5M in tBuOH, 0.31 mL, 1.57 mmol). The reaction was allowed to warm to room temperature and stirred for 48 hours. The reaction was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine and dried over sodium sulfate. The crude product was dry loaded on celite and purified by silica column chromatography with a gradient of 1:49 MeOH: DCM to 3:47 MeOH: DCM. The product was obtained as a white solid in 92% yield (89.5 mg). 1H-NMR (CD3Cl, 500 MHz): δ δ 5.22 (d, 2H), 3.75 (s, 1H), 3.67 (dd, 1H), 3.42 (s, 1H), 2.93 (dd, 2H), 2.71 (s, 1H), 1.97 (m, 1H), 1.82-1.55 (m, 8H), 1.52-1.42 (m, 10H), 1.41-1.32 (m, 6H), 1.28 (m, 3H), 1.19 (s, 1H), 1.02 (s, 3H), 0.91 (m, 3H), 0.87 (s, 3H).13C-NMR (CD3Cl, 125 MHz): δ 160.79, 152.37, 108.40, 81.60, 79.29, 73.10, 56.73, 53.23, 45.69, 43.53, 42.37, 40.19, 39.25, 38.96, 37.58, 36.45, 35.19, 27.83, 19.89, 18.32, 18.13. HRMS(ESI): m / z calc. for [M+H]+= 372.2539, found: 372.2540. A 1 L round bottom flask was charged with DCM (374 mL) then TFAA (2.90 mL), TFA (2.07 mL) and hydrogen peroxide (0.83 mL). The starting material (288.9 mg, 0.814 mmol) was dissolved in DCM (55 mL) and added to the 1 L round bottom flask. The reaction was stirred for 40 minutes and quenched with saturated sodium bicarbonate. The reaction mixture was washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated by rotatory evaporation. The crude product was dry loaded on celite and purified via silica column chromatography with a gradient of 1.2% MeOH / DCM to 1.6% MeOH / DCM. The product was isolated as a white solid in a 38% yield (116.1 mg). 1H-NMR (CD3OD, 500 MHz): δ 3.69 (d, 1H), 3.67 (s, 1H), 3.56-3.37 (d, 1H), 2.97 (d, 1H), 2.68 (dd, 1H), 1.95 (d, 1H), 1.85 (d, 1H), 1.80-1.67 (m, 5H), 1.63 (dp, 2H), 1.49 )m, 2H), 1.41 (tt, 3H), 1.34 (m, 1H), 1.27 (tt, 1H), 1.14 (d, 1H), 0.99 (s, 3H), 0.94 (s, 3H).13C-NMR (CD3OD, 125 33 500.151WO1 UIUC2023-116-02(PCT) MHz): δ 221.18, 153.78, 78.13, 77.87, 77.61, 74.47, 62.98, 56.97, 56.01, 54.44, 49.05, 41.72, 41.10, 39.14, 37.83, 37.42, 35.98, 32.15, 27.01, 19.61, 19.25, 17.71, 14.80. HRMS(ESI): m / z calc. for [M+H]+= 372.2539, found: 372.2539. A round bottom flask was charged with isosteviol (145.2 mg, 0.41 mmol) and sodium carbonate (332 mg, 3.13 mmol) followed by the addition of DCM (8.17 mL). The solution was cooled to 0°C and peracetic acid (0.43 mL, 2.04 mmol) as a 32% solution in acetic acid was added. The mixture was stirred for 20.5 hours and quenched with a saturated sodium bicarbonate solution. The quenched reaction mixture was acidified to pH=3 with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was dried loaded on celite and purified by silica gel column chromatography with a gradient of 1:20:79 MeOH: EtOAc: Hex to 1:70:29 MeOH: EtOAc: Hex. The product was obtained as a white solid in an 8% yield (12.7 mg) with 64% rsm (93.4 mg). 1H-NMR (CD3Cl, 500 MHz): δ 5.67 (t, 1H), 3.61 (dd, 1H), 2.99 (dd, 1H), 2.94 (dd, 1H), 2.72 (s, 1H), 1.93 (m, 3H), 1.69 (m, 1H), 1.59 (m, 4H), 1.50 (m, 5H), 1.41-1.28 (m, 5H), 1.27 (s, 3H), 1.26-1.13 (m, 4H), 0.95 (s, 1H), 0.82 (s, 3H).13C-NMR (CD3Cl, 125 MHz): δ 172.40, 152.35, 80.31, 73.16, 57.47, 56.73, 47.80, 43.75, 42.15, 39.57, 38.83, 38.28, 37.74, 37.45, 36.38, 35.03, 28.29, 27.66, 18.35, 18.08, 17.95, 16.46. HRMS(ESI): m / z calc. for [M+H]+= 372.2539, found: 372.2542. To a stirred solution of SM (488 mg, 1.37 mmol) in DCM:MeOH (3:1, 13.5 mL) at 0 °C was added propargylamine (0.7 mL, 11.0 mmol) dropwise. Acetic acid (1 mL) was added dropwise until pH 5 was reached and the temperature was allowed to warm to rt. After 15 h, the reaction was cooled to 0 °C and NaBH3CN (260 mg, 4.11 mmol) was added. Additional propargylamine (0.7 mL) and acetic acid (1 mL) were added as progress became sluggish to react with residual starting material. After 15 hours, the reaction was diluted with EtOAc and dry-loaded onto Celite. Column chromatography in MeCN / DCM followed by additional purification with a gradient of 40:58:2 to 45:53:2 EtOAc:hexanes:Et3N afforded the product as a white foam in 13% yield (73 mg). 34 500.151WO1 UIUC2023-116-02(PCT)1H NMR (500 MHz, CDCl3) δ 5.72 (d, J = 6.9 Hz, 1H), 3.68 (dd, J = 13.8, 7.2 Hz, 1H), 3.53 – 3.45 (m, 1H), 3.35 (dd, J = 17.0, 2.4 Hz, 1H), 3.01 (ddd, J = 13.7, 5.9, 1.4 Hz, 1H), 2.93 (dd, J = 10.8, 5.5 Hz, 1H), 2.77 (s, 1H), 2.20 (t, J = 2.4 Hz, 1H), 2.07 (s, 0H), 1.77 – 1.61 (m, 9H), 1.60 – 1.49 (m, 5H), 1.44 – 1.34 (m, 3H), 1.28 (dd, J = 12.4, 3.1 Hz, 1H), 1.25 (s, 1H), 1.23 – 1.16 (m, 1H), 1.04 – 0.95 (m, 4H), 0.94 (s, 3H), 0.92 – 0.89 (m, 6H), 0.82 (td, J = 12.9, 3.8 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 152.33, 82.77, 79.47, 77.55, 72.99, 71.09, 65.88, 57.10, 57.03, 56.80, 42.66, 42.40, 41.71, 41.50, 40.54, 39.39, 37.82, 37.70, 37.41, 36.59, 34.13, 27.90, 25.40 (d, J = 3.0 Hz), 20.13, 17.94, 15.69. HRMS(ESI): m / z calc. for [M+H]+= 395.3062, found: 395.3058. In round-bottom flask, starting material (317 mg, 1.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled in an ice bath. Lithium aluminum hydride (LiAlH4) (114 mg, 3.0 mmol, 3.0 equiv.) was added slowly and the mixture stirred for 20 mins before the flask was equipped with a reflux condenser. The reaction was heated to 70 ºC for 5-10 h. The reaction was cooled in an ice bath and quenched with water followed by 1 M aqueous NaOH and the mixture stirred for 10 min at 0 ºC. The aqueous layer was extracted with EtOAc until no product was seen in the aqueous layer. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was cooled in an ice bath and a 4 M solution of HCl in dioxane (0.25 mL, 1.0 mmol, 1.0 equiv.) were added and stirred for 10 min and then concentrated in vacuo. In a round-bottom flask to the crude intermediate (254 mg, 0.75 mmol, 1.0 equiv.) was added DCM (10 mL) under a nitrogen atmosphere and cooled in an ice bath. Triethylamine (TEA) (0.41 mL, 3.0 mmol, 4.0 equiv.) was added followed by dropwise addition of 2-chloroacetyl chloride (90 μL, 1.125 mmol, 1.5 equiv.). The reaction was gradually warmed up to room temperature and stirred for 18 h when it was carefully quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc until no product was seen in the aqueous layer indicated from the LCMS trace. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100:0 to 60:40 Hexanes / EtOAc (1% MeOH)) to afford the product in 43% yield (121 mg) over two steps as a white solid. 1H NMR (500 MHz, CDCl3 / MeOD) δ 6.87 (t, J = 6.3 Hz, 1H), 4.78 (t, J = 2.4 Hz, 1H), 4.62 (s, 1H), 3.86 (s, 2H), 3.49 (dd, J = 13.5, 7.1 Hz, 1H), 2.81 (dd, J = 13.6, 5.6 Hz, 1H), 2.01 (dt, J = 17.5, 2.9 Hz, 1H), 1.93 – 1.84 (m, 2H), 1.68 (d, J = 13.3, 4.2 Hz, 1H), 1.65 – 1.17 (m, 12H), 1.08 (dd, J = 11.4, 2.4 Hz, 1H), 0.91 (s, 3H), 0.86 – 0.77 (m, 3H), 0.73 (s, 3H), 0.64 (ddd, J = 13.0, 3.8 Hz, 35 500.151WO1 UIUC2023-116-02(PCT) 1H).13C NMR (126 MHz, CDCl3 / MeOD) δ 167.0, 155.3, 102.6, 79.6, 56.7, 54.8, 47.4, 46.1, 42.4, 42.3, 41.30, 41.32, 40.0, 39.2, 38.9, 37.5, 36.3, 27.4, 20.0, 19.9, 17.9, 17.8. HRMS (ESI): m / z calc for C22H35NO2Cl [M+H]+: 380.2356, found: 380.2372. In round-bottom flask to starting material (95 mg, 0.32 mmol, 1.0 equiv.) as a free base, was added DCM (20 mL) under a nitrogen atmosphere and cooled in an ice bath. Triethylamine (TEA) (0.13 mL, 0.95 mmol, 3.0 equiv.) was added followed by dropwise addition of acryloyl chloride (39 μL, 0.47 mmol, 1.5 equiv.). The reaction was gradually warmed up to room temperature and stirred for 18 h when it was carefully quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc until no product was seen in the aqueous layer indicated from the LCMS trace. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100:0 to 50:50 Hexanes / EtOAc (1% MeOH)) to afford the product in 36% yield (40 mg). 1H NMR (500 MHz, CDCl3 / MeOD) δ 6.23 (s, 1H), 6.22 (s, 1H), 5.63 (t, J = 6.0 Hz, 1H), 4.97 (d, J = 2.3 Hz, 1H), 4.81 (d, J = 2.3 Hz, 1H), 3.72 (d, J = 13.5 Hz, 1H), 2.99 (d, J = 13.5 Hz, 1H), 2.20 (d, J = 17.8 Hz, 1H), 2.14 – 2.06 (m, 2H), 1.92 – 1.37 (m, 12H), 1.28 (d, J = 10.7 Hz, 1H), 1.12 (s, 3H), 1.00 (t, J = 12.6, 8.7 Hz, 2H), 0.95 (dd, J = 13.6, 4.4 Hz, 1H), 0.91 (s, 3H), 0.83 (ddd, J = 13.1, 3.8 Hz, 1H).13C NMR (126 MHz, CDCl3 / MeOD) δ 166.9, 155.2, 130.5, 125.6, 102.4, 79.5, 56.7, 54.7, 47.3, 46.0, 41.4, 41.3, 41.2, 40.0, 39.1, 38.8, 37.7, 36.1, 27.3, 19.8, 17.9, 17.7. HRMS (ESI): m / z calc for C23H36NO2 [M+H]+: 358.2746, found: 358.2750. Example 2. Characterizations. Data from the structure activity relationship (SAR) of synthesized compounds, and toxicological data for selected compounds is shown in the tables that follow. 36 500.151WO1 UIUC2023-116-02(PCT) Table 1. Structure-Activity Relationship (SAR) Studies. A. Electrophile Modification (ES-2 IC50(nM) tested for activity only): 330 ± 30 160 ± 10 >30,000 >60,000 B. Electrophile Modification (Activity + Selectivity – IC50’s (nM) for shown cell lines and fold- difference): OPM-2 81.4 ± 7.5 95.8 ± 0.7 110 ± 16 HCT116 14,800 ± 600 14,400 ± 2,100 2,230 ± 230 Fold Diff. 180 150 20 C. Hydroxyl Group / D-Ring Modifications (IC50’s (nM) for shown cell lines and fold-difference): OPM-2 237.8 ± 8.7 125.5 ± 9.4 58 ± 3 53.1 ± 5.1 37 500.151WO1 UIUC2023-116-02(PCT) HCT116 11,300 ± 950 12,500 ± 850 321 ± 32 11,200 ± 920 Fold Diff. 50 100 210 D. Isosteviol Scaffold Rearrangement IC50’s (nM) for shown cell lines and fold-difference): OPM-2 25.8 ± 1.7 189.7 ± 1.6 118.3 ± 7.3 187 ± 23 HCT116 13,100 ± 1,200 30,100 ± 810 16,000 ± 4,500 8,300 ± 32 Fold Diff. 508 158 136 44 OPM-2 194 ± 8 73 ± 14 41.0 ± 4.2 40.3 ± 7.9 HCT116 12,700 ± 1,300 8,240 ± 460 1,915 ± 120 1,350 ± 150 Fold Diff. 65 112 47 53 Table 2. Additional compounds for SAR studies. Chemoenzymatic Oxidations: 38 500.151WO1 UIUC2023-116-02(PCT) Extrapolation of Hit Compounds: Table 3. Maximum Tolerated Dose (MTD) and Pharmacokinetic (PK) Studies. Example 3. Pharmaceutical Dosage Forms. The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'): (i) Tablet 1 mg / tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 39 500.151WO1 UIUC2023-116-02(PCT) (ii) Tablet 2 mg / tablet 'Compound X' 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg / capsule 'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg / mL) mg / mL 'Compound X' (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg / mL) mg / mL 'Compound X' (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 0.1 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg / can 'Compound X' 20 Oleic acid 10 Trichloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000 (vii) Topical Gel 1 wt.% 'Compound X' 5% Carbomer 934 1.25% Triethanolamine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100g 40 500.151WO1 UIUC2023-116-02(PCT) (viii) Topical Gel 2 wt.% 'Compound X' 5% Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100g (ix) Topical Ointment wt.% 'Compound X' 5% Propylene glycol 1% Anhydrous ointment base 40% Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100g (x) Topical Cream 1 wt.% 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100g (xi) Topical Cream 2 wt.% 'Compound X' 5% Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5% Isopropyl palmitate 2 % Methyl Paraben 0.2% Purified water q.s. to 100g These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest. All publications, patents, and patent documents cited herein are incorporated by reference as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and 41 500.151WO1 UIUC2023-116-02(PCT) preferred embodiments and techniques. However, many variations and modifications may be made while remaining within the spirit and scope of the invention. While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. 42 500.151WO1 UIUC2023-116-02(PCT)

Claims

What is claimed is:

1. A compound of Formula I:or a salt thereof; wherein: G1is CH2, CHORa, or C=O; G2is C=CH2, C=O, CHORb, CHN(Rc)2, C(CH2O)–, –O(C=O)–, or C(ORa)CH2ORa; each Rais independently H, –(C1-C6)alkyl, or –(C=O)(C1-C6)alkyl; each Rbis independently H, –(C1-C6)alkyl, –(C=O)(C1-C6)alkyl, or –(C=O)C ^CH; each Rcis independently H, –(C1-C6)alkyl, or –CH2C ^CH; J1, J2, and J3are each independently H or ORa; R1is –CH2X1(C=O)R3or –CO2(C1-C6)alkyl, wherein X1is NR4or O; R2is ORa, CH3, CH2ORb, or CHO; alkyl,2or CH2X wherein X2is halo; and R4is H or –(C1-C6)alkyl.

2. The compound of claim 1 wherein G1is CH2 or CHORa.

3. The compound of claim 1 wherein G2is C=CH2, C=O, or CHN(Rc)2.

4. The compound of claim 1 wherein J1, J2, and J3are each H.

5. The compound of claim 1 wherein R1is –CH2X1(C=O)R3and R3is –C ^CH.

6. The compound of claim 1 wherein R1is –CH2NH(C=O)C ^CH.

7. The compound of claim 1 wherein R2is ORaor CH3. 43 500.151WO1 UIUC2023-116-02(PCT)8. The compound of claim 1 wherein the compound is a compound of Formula II:wherein X3is CH2or O; or a salt thereof.

9. The compound of claim 8 wherein X1is NH.

10. The compound of claim 8 wherein R3is –C ^CH.

11. The compound of claim 1 wherein the compound is Steviokine:salt thereof.

12. The compound of claim 1 wherein the compound is:44 500.151WO1 UIUC2023-116-02(PCT)13. The compound of claim 1 wherein the compound is:45 500.151WO1 UIUC2023-116-02(PCT)15. A composition comprising a compound of any one of claims 1-14 and a pharmaceutically acceptable diluent or carrier. 46 500.151WO1 UIUC2023-116-02(PCT)16. The composition of claim 15 wherein the composition comprises only a single diastereomer of the compound to an extent of at least 95%.

17. A method of treating a cancer comprising administering to a subject having the cancer a therapeutically effective amount of a compound of any one of claims 1-14, wherein the cancer is thereby treated.

18. The method of claim 17 wherein the cancer is blood cancer, brain cancer, breast cancer, bone cancer, cervical cancer, colon cancer, esophageal adenocarcinoma, glioblastoma, head and neck cancer, hematopoietic cancer, kidney cancer, leukemia, liver cancer such as hepatocellular carcinoma, lung cancer, lymphoma, melanoma, multiple myeloma, muscle cancer, oral cavity cancer, ovarian cancer, pancreatic cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer, rhabdomyosarcoma, sarcoma, skin cancer, splenic cancer bladder cancer, thyroid cancer, urothelial cancer, urinary bladder cancer, or uterine cancer.

19. The method of claim 17 wherein the cancer is multiple myeloma or leukemia.

20. The method of claim 17 wherein the cancer is kidney cancer, liver cancer, or prostate cancer. 47 500.151WO1 UIUC2023-116-02(PCT)

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